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Patent 2220927 Summary

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(12) Patent: (11) CA 2220927
(54) English Title: TISSUE ADHESIVE SUITABLE FOR SPRAY APPLICATION
(54) French Title: ADHESIF POUR TISSUS, APPLIQUE PAR PULVERISATION
Status: Deemed expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61L 17/00 (2006.01)
  • A61B 17/00 (2006.01)
  • A61L 24/10 (2006.01)
(72) Inventors :
  • UCHIDA, TAKANORI (Japan)
  • KAETSU, HIROSHI (Japan)
  • FUKUNAGA, NOBUTO (Japan)
  • SHINYA, NORIKO (Japan)
  • SAKAMOTO, TAKAHIRO (Japan)
(73) Owners :
  • JURIDICAL FOUNDATION THE CHEMO-SERO-THERAPEUTIC RESEARCH INSTITUTE (Japan)
(71) Applicants :
  • JURIDICAL FOUNDATION THE CHEMO-SERO-THERAPEUTIC RESEARCH INSTITUTE (Japan)
(74) Agent: NORTON ROSE FULBRIGHT CANADA LLP/S.E.N.C.R.L., S.R.L.
(74) Associate agent:
(45) Issued: 2008-04-22
(86) PCT Filing Date: 1997-03-14
(87) Open to Public Inspection: 1997-09-18
Examination requested: 2002-03-08
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/JP1997/000818
(87) International Publication Number: WO1997/033633
(85) National Entry: 1997-11-13

(30) Application Priority Data:
Application No. Country/Territory Date
87566/1996 Japan 1996-03-15

Abstracts

English Abstract





An adhesive for tissue capable of uniformly forming a high
concentration of fibrin so as to provide a high closing effect is
disclosed. The adhesive for tissue comprises a fibrinogen solution and a
thrombin solution which solutions are separated from each other. The
adhesive is to be mixed and spray coated together with a sterile gas and
has a volume ratio of the fibrinogen solution to the thrombin solution of
about 2:1 to 10:1. This adhesive is to be sprayed together with a
sterile gas for the adhesion or closing of living tissue of a human being
or anima 1.


French Abstract

L'invention concerne un adhésif pour tissus, capable de former de la fibrine d'une manière dense et uniforme et présentant de bonnes propriétés occulsives. L'adhésif pour tissus est mélangé avec un gaz aseptique et le mélange est appliqué au tissu. L'adhésif pour tissu a deux composants, une solution de fibrinogène et une solution de thrombine. Le rapport volumique de la solution de fibrinogène sur la solution de thrombine est dans la plage de 2:1-10:1. Cet adhésif pour tissus est utilisé en médecine humaine ou vétérinaire, pour faire adhérer des tissus, ou comme produit d'occlusion.

Claims

Note: Claims are shown in the official language in which they were submitted.





What is claimed is:

1. An adhesive for adhering or closing a wound
in a living human or animal tissue, the adhesive being
formed at the wound by simultaneously spraying and
mixing together onto the wound, a separate fibrinogen
solution and a separate thrombin solution together with
a sterile gas, wherein the volume ratio of the
fibrinogen solution to the thrombin solution is about
2:1 to 5:1, the fibrinogen solution having a
concentration of 4 to 15% (w/v, 40 to 150 mg/ml) and
the thrombin solution having a concentration of 100 to
10,000 units/ml (NIH units).


2. The adhesive of claim 1, wherein the
fibrinogen solution has a concentration of 7 to 12%
(w/v, 70 to 120 mg/ml).


3. The adhesive of claim 1 or 2, wherein the
thrombin solution has a concentration of 250 to 5,000
units/ml (NIH units).


4. The adhesive of any one of claims 1 to 3,
wherein the fibrinogen solution contains at least one
viscosity-lowering agent.


5. The adhesive of claim 4, wherein the
viscosity-lowering agent is arginine.


6. The adhesive of claim 5 which contains 0.1 to
1.0 M of arginine.



-15-




7. The adhesive of claim 6 which contains 0.1 to
0.5 M of arginine.


8. A spray device for simultaneously and
separately spraying a fibrinogen solution and a
thrombin solution toward a living tissue of a human
being or animal to mix them on said living tissue,
comprising:
.cndot.(i) a spray head having a pair of two sterile gas-
jet openings at the forward portion thereof and a
pair of two syringe-connecting ports at the
backward portion thereof; and further having a
sterile gas-feeding passage at the backward
portion thereof so that sterile gas is jetted
through said sterile gas-jet openings;
.cndot.(ii) a pair of tubes provided inside the spray
head, the one end of said tube positioning inside
said syringe-connecting port and opening at the
backward end portion of said syringe-connecting
port, and the other end of said tube positioning
inside said sterile gas-jet opening and opening at
the forward end portion of said sterile gas-jet
opening;
.cndot.(iii) a pair of syringes each having barrels and
plungers for pushing the solutions contained in
said barrels forward, the forward ends of said
barrels being connected with said tubes
respectively at said syringe-connecting ports,
wherein the ratio of the cross section of said
barrel to that of said barrel is 2:1 to 5:1; and



-16-




.cndot.(iv) an integrally operating means provided at the
backward end of said plungers so as to integrally
move said plungers;
wherein said barrel contains said fibrinogen
solution having a fibrinogen concentration of 4 to 15%
(w/v, 40 to 150 mg/ml), and said barrel contains said
thrombin solution having a thrombin concentration of
100 to 10,000 units/ml (NIH units).


9. The device of claim 8, wherein the fibrinogen
solution has a concentration of 7 to 12% (w/v, 70 to
120 mg/ml).


10. The device of claim 8 or 9, wherein the
thrombin solution has a concentration of 250 to 5,000
units/ml (NIH units).


11. The device of any one of 8 to 10, wherein
said fibrinogen solution contains at least one
viscosity-lowering agent.


12. The device of claim 11, wherein said
viscosity-lowering agent is arginine.


13. The device of claim 12, wherein said
fibrinogen solution contains 0.1 to 1.0 M of arginine.

14. The device of claim 13, wherein said

fibrinogen solution contains 0.1 to 0.5 M of arginine.



-17-

Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02220927 1997-11-13
SPECIFICATION
Title of the Invention:

Tissue Adhesive Suitable for Spray Application

Technical Field of the Invention:

The present invention relates to an adhesive for tissue, which is
to be used in the form of a two-pack type preparation and which is
suitable for the uniform application of the adhesive at a concentration

higher than that of an ordinary adhesive. _In particular, the present
invention relates to an adhesive for tissue (hereinafter referred to as
tissue adhesive) suitable for the use in a method wherein a protein
solution containing fibrinogen as the essential component and a thrombin
solution are sprayed and also suitable for lowering the volume ratio ofa

thrombin solution to a fibrinogen solution of a high concentration so as
to uniformly form fibrin of a high-concentration, whereby obtaining a
high closing effect.

Background of the Invention:

Fibrinogen is a clotting factor having a very important role in
the final stage of the so-called blood-coagulation cascade. In the
activation of, for example, the blood clotting system after a damage,
soluble fibrinogen is converted, by thrombin, into insoluble fibrin which
has an important role of contributing to the hemostasis and curing of a

wound. Recently, a tissue adhesive was developed taking advantage of this
theory in the final phase of the blood clotting, and it is now used as an
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CA 02220927 1997-11-13

adhesive in place of a suture of a soft organ such as liver or spleen or
as a suture assistant in a surgical operation. A tissue.adhesive is
widely used also in other clinical situation.

For the application of the tissue adhesive to an affected part of
the body, a "sequential method" wherein a fibrinogen solution and a
thrombin solution are applied alternately to form a laminate coat or a
"simultaneous method" wherein both the fibrinogen solution and thrombin
solution are applied simultaneously to mix them together was mainly
employed. However, the sequential method has a problem in that a major

part of the fibrinogen solution flows down prior to the formation of a
fibrin gel, and also the simultaneous method has a problem in that the
formed fibrin gel is heterogeneous. Therefore, the effect of the tissue
adhesive was limited in both the sequential method and simutaneous method.

Recently, a spray method has just started to be spread for solving
the above-described problems. In this method, a fibrinogen solution and
a thrombin solution in each syringe are simultaneously ejected together
with a sterile gas to spray these two solutions in the form of a mist
mixture. A preferred example of the devices for this method is described
in International Patent Publication (PCT W094-07420). However, even such

a spray method has a problem to be solved for obtaining a complete effect
of the tissue adhesive when a strong adhesion and closing effect are
demanded in, for example, the treatment of great vessels and also the
treatment of air leak in the lungs.

Investigations were made for improving the effect of the tissue
adhesive by increasing the concentration of fibrinogen to find that,
although the clotting strength and adhesive power of the fibrin gel
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CA 02220927 2006-02-21

obtained by the sequential method are increased as the final
concentration of fibrinogen in the mixture of the two components is
increased,, they are no more increased even when the final concentration of
fibrinogen is increased to about 4$ or higher [see "Kiso to Rinsho"

(Basic and Clinical Report), 20, 2399 to 2405 (1986), and 23, 3735 to
3743 (1989)]. However, when the sequential method is employed, the
fibrin gel obtained by such a test cannot be uniformly applied. Thus, it
cannot be said that the advantage of the increase in the final
concentration of fibrinogen has been put to practical use.

Japanese Patent Unexamined Published Application (hereinafter
referred to as "J. P. KOKAI") No. Sho 61-293443 discloses a method for
increasing the final concentration of fibrinogen in the mixture of the
two components by changing the mixing ratio of the fibrinogen solution to
the thrombin solution in its specification (in particular, in the "test

results" in the detailed description of the Invention). In this
specification, it is described that the limiting tensile strength depends
on the final concentration of fibrinogen after mixing the two components.

However, in these tests, the adhesive is applied by so-called
"mixing method" and, in addition, the final concentration of thrombin in
the formation of the fibrin gel after mixing the two components is as low

as 1 to 2 units/ml. Such a low thrombin concentration is far apart from
the thrombin concentration (250 to 500 units/ml) actually employed in the
clinical sites. It is known that particularly when the thrombin
concentration is low, the clotting of fibrinogen necessitates a long

period of time and, in addition, a sufficient hemostasis effect cannot be
obtained in the closing treatment of the tissue. Although a test wherein
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CA 02220927 1997-11-13

the final concentration of thrombin after mixing the two components is as
high as 500 units/ml is described therein, it is stated therein that the
limiting tensile strength could not be determined. This fact suggests
that the tests given in J. P. KOKAI No. Sho 61-293443 are unsuitable for

the determination of the effects of the tissue adhesive to be used in a
clinical site.

The main object of the invention disclosed in J. P. KOKAI No. Sho
61-293443 is to provide a device for preparing a fibrinogen solution from
a freeze-dried preparation previously charged in a syringe, which is

capable of shortening the dissolution time without reducing the limiting
tensile strength of the adhesive. In this invention, the mixing ratio is
varied so that a limiting tensile strength equal to that of an ordinary
product (a concentration is 10 % before the mixing) can be obtained even
when the concentration of the fibrinogen solution is lowered. Therefore,

the concentration described therein is not the practical one, and this
invention does not provide any means for adhering a tissue which is
suitable for the actual use for particularly obtaining a high effect of
closing the wound.

Therefore, the object of the present invention is to provide a
tissue adhesive suitable for spray application, which is to be used in
the form of a two-pack preparation and which can be used at a high
concentration and uniformly sprayed.

Another object of the present invention is to provide a tissue
adhesive capable of uniformly forming fibrin of a high concentration to
provide a high closing effect.

After intensive investigations made for the purpose of attaining
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CA 02220927 2007-03-29

the above-described objects, and on the basis of an
idea that the spray method wherein the fibrinogen
solution and thrombin solution can be homogeneously
mixed together is the best method for the application
of the tissue adhesive, the inventors have found the
following fact: for improving the effect of fibrinogen
by increasing the final concentration of fibrinogen in
the mixture of the two components, it is effective that
the concentration of fibrinogen which can be sprayed is
made as high as possible and also that the mixing ratio
of the fibrinogen solution and thrombin solution is
changed. Further, the structure of a device for
conducting this method has been made clear, and the
present invention capable of providing the tissue
adhesive suitable for use in a method wherein a
remarkable effect is obtained has been completed.
Summary of the Invention
The present invention relates to a tissue adhesive
comprising a fibrinogen solution and a thrombin
solution which solutions are separate from each other
and to be mixed and sprayed together by means of a
sterile gas for adhering or closing a wound of a living
tissue of a human being or an animal, wherein the
volume ratio of the fibrinogen solution to the thrombin
solution is about 2:1 to 10:1, preferably 2:1 to 5:1.
The fibrinogen solution preferably has a
concentration of 4 to 15% (w/v, 40 to 150mg/ml) and the
thrombin solution preferably has a concentration of 100
to 10,000 units/ml (NIH units).

- 5 -


CA 02220927 2007-03-29

More particularly, the invention provides an
adhesive for adhering or closing a wound in a living
human or animal tissue, said adhesive being formed at
the wound by simultaneously spraying and mixing
together onto the solution and a separate thrombin
solution together with a sterile gas, wherein the
volume ratio of the fibrinogen solution to the thrombin
solution is about 2:1 to 10:1.
In another aspect, the invention provides a spray
device for simultaneously and separately spraying a
fibrinogen solution and a thrombin solution toward a
living tissue of a human being or animal to mix them on
said living tissue, comprising:
=(i) a spray head having a pair of two sterile gas-
jet openings at the forward portion thereof and a
pair of two syringe-connecting ports at the
backward portion thereof; and further having a
sterile gas-feeding passage at the backward
portion thereof so that sterile gas is jetted
through said sterile gas-jet openings;
= (ii) a pair of tubes provided inside the spray
head, the one end of said tube positioning inside
said syringe-connecting port and opening at the
backward end portion of said syringe-connecting
port, and the other end of said tube positioning
inside said sterile gas-jet opening and opening at
the forward end portion of said sterile gas-jet
opening;
= (iii) a pair of syringes each having barrels and
plungers for pushing the solutions contained in
said barrels forward, the forward ends of said

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CA 02220927 2007-03-29

barrels being connected with said tubes
respectively at said syringe-connecting ports,
wherein the ratio of the cross section of said
barrel to that of said barrel is 2:1 to 10:1
preferably 2:1 to 5:1; and (iv) an integrally
operating means provided at the backward end of
said plungers so as to integrally moving said
plungers;
wherein said barrel contains said fibrinogen
solution having a fibrinogen concentration of 4 to 15%
(w/v, 40 to 150 mg/ml), and said barrel contains said
thrombin solution having a thrombin concentration of
100 to 10,000 units/ml (NIH units).

Brief Description of the Drawings:
Fig. 1 is a drawing showing the method for
determining the closing effect.
Fig. 2 is a graph showing the change in closing
effect by changing the mixing ratio in both spray
method and sequential method.

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CA 02220927 1997-11-13

Fig. 3 is a plan view of a device suitable for spraying the tissue
adhesive of the present invention.

Preferred Embodiments for Practicing the Invention:

The object of the present invention is to obtain a high closing
effect by changing the mixing volume ratio of the fibrinogen solution to
the thrombin solution of 1:1 which was conventionally used in the prior
art so as to reduce the volume ratio of the thrombin solution to the
fibrinogen solution, so that when both the solutions are sprayed, fibrin

of a high concentration is uniformly formed. From this viewpoint, the
suitable concentrations of the fibrinogen solution and the thrombin
solution are 4 to 15 % (w/v, 40 to 150 mg/ml), preferably 7 to 12 0(w/v,
70 to 120 mg/ml), and 100 to 10,000 units/ml (Japanese Phamacopoeia or NIH
units based on the US Standard Thrombin), preferably 250 to 5,000

units/ml (NHI units), respectively. The mixing ratio of them is
preferably about 2:1 to 10:1 (volume ratio), particularly 2:1 to 5:1.
Although it is difficult to mix the two components in a precise

mixing ratio other than 1:1 by using the two separate syringes, such a
mixing can be conducted preferably by using an application device
suitable for the tissue adhesive of the present invention, which is shown
in Fig. 3.

In this device, a syringe containing the fibrinogen solution has
an effective stroke having a length equal to that of another syringe
containing the thrombin solution, and the cross section of the syringe

containing the fibrinogen solution is about 2 to 10 times as large as
that of the syringe containing the thrombin solution. By operating the
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CA 02220927 1997-11-13

pistons of both syringes integrally, both solutions in a volume ratio
determined according to the cross sections of the two syringes are
extruded through a pipe to a sterile gas jet opening in a spray head to
form a mist. The adhesive is thus spray coated.

The present invention provides a more desirable mode of the tissue
adhesive suitable for the spray coating. When a fibrinogen solution is
to be sprayed with a spraying device, it was difficult to spray the
fibrinogen solution having a concentration of as high as above 10 0(100
mg/m 1) in the prior art. However, the viscosity of the fibrinogen

solution can be remarkably lowered by adding a viscosity-lowering agent to
the solution so that the solution can be sprayed in a suitable manner.
Particularly when a high adhesion strength is necessitated, the uniform
spraying is made possible by lowering the viscosity even when the
fibrinogen content is about 10 0(100 mg/ml) or higher. The object of
the invention can be thus attained. _

By increasing the concentration of the fibrinogen solution to be
mixed with the thrombin solution, the final concentration of fibrinogen
which was increased by changing the mixing ratio is further increased and
the effect thereof is further improved. The viscosity-lowering agents

which are not particularly limited herein include, for example, guanidino
group-containing substances such as arginine and guanidine. Arginine or
the like is particularly preferably used. The viscosity-reducing agents
are usable either alone or in combination of two or more of them. The
amount of the viscosity-reducing agent is preferably 0.1 to 1.0 M,
particularly preferably 0.1 to 0.5 M.

According to the present invention, the tissue adhesive having a
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CA 02220927 1997-11-13

high closing effect can be obtained by uniformly forming fibrin of a high
concentration.

The following Test Examples and Working Examples will further
illustrate the present invention, which by no means limit the scope of the
present invention.

Examples
Test Example 1

The test was conducted by using "Bolheal" [a product of the Chemo-
Sero-therapeutic Research Institute] which is a commercial two-component
adhesive for living tissue. This preparation had a fibrinogen
concentration of 8 % and thrombin concentration of 250 units/mi.

The closing effect was evaluated by means of a device shown in Fig.
1. In the test, five holes having a diameter of 1.2 mm were bored in a
cap of a plastic test tube which was then connected with a manometer and a

compressing syringe. A tissue adhesive comprising the two solutions in a
varied mixing ratio was applied to the cap by the spray method or
sequential method. Ten minutes after the formation of the adhesive, air
in the tube was compressed with the syringe and the pressure (burst

pressure: mmHg) at the moment of starting the air leak through the fibrin
gel was recorded. The mixing ratio of the fibrinogen solution to the
thrombin solution was 1:1 or 5:1. The amount of the fibrinogen solution
used was 0.85 ml in all the cases.

As shown in Fig. 2, when the mixing ratio was changed from 1:1 to
- 5:1, the burst pressure was remarkably elevated from 287 mmHg to 445 mmHg
in the spray method, while it was lowered in the sequential method. The
- 8 -


CA 02220927 1997-11-13

burst pressure of 445 mmHg obtained by changing the mixing ratio in the
spray coating was an extremely high pressure which could not be obtained
in the prior art.

Test Example 2

The test was conducted by using "Bolheal" [a product of the Chemo-
Sero-therapeutic Research Institute] which is a commercial two-component
adhesive for living tissues. This preparation had a fibrinogen
concentration of 8 % and thrombin concentration of 250 units/ml.

The closing effect was evaluated on the basis of the air leak-
preventing capacity in the lungs of rats. In the test, a tracheal tube
was inserted into the trachea of a rat and fixed therein at one end
thereof by the ligation. The other end of the tracheal tube was connected
with a cannula, trigonal stopcock, manometer and compressing syringe.

After confirming no air leak, the pressure was controlled with the syringe
so that the manometer indicated 15 mmHg. A hole having a diameter of 1.2
mm was bored in the lung with a needle, and a tissue adhesive having a
given mixing ratio was spray coated on the air leak portion. 10 minutes
after the formation of the adhesive, saline was applied to the lung, the

pressure was elevated with the syringe, and the pressure (burst pressure:
mmHg) under which the air leak of the lung began was recorded. The mixing
ratio of the fibrinogen solution to the thrombin solution was 1:1 or 5:1.
The amount of the fibrinogen solution used was 0.15 ml in all the cases.

As shown in the following Table 1, the burst pressure was
remarkably elevated from 27.8 mmHg to 49.4 mmHg by changing the mixing
ratio from 1:1 to 5:1.

- 9 -


CA 02220927 1997-11-13
Table 1

Burst pressure Order of times of determination

(mmHg) 1 2 3 4 5 6 7 8 Average S.D.
Mixing ratio

1:1 16 25 31 32 43 32 20 23 27.8 + 8.5
5:1 40 64 42 40 67 42 42 58 49.4 11.6
Test Example 3

A solution having a coagulating protein concentration of 7.5 toll.
1 g(w/v) was prepared from fibrinogen prepared by a combination of a
cold ethanol precipitation method with a method wherein the solubility of
fibrinogen is lowered by glycine or by a glycine precipitation method

wherein glycine is used alone. The viscosity (mPa = s) of each solution
was determined at 37 C to find that a high viscosity resulted depending on
the coagulating protein concentration. Particularly when the coagulating
protein concentration was 11.1 %, the viscosity was as high as 152.2 mPa
= s. However, when arginine was added to the 11.1% solution so that the

final arginine concentration would be 0.1 to 0.5 M, the viscosity became
77.4 to 84.2 mPa = s. This fact proved the viscosity-lowering effect of
arginine. The results were as shown in the following Table 2.


- 1 0 -


CA 02220927 1997-11-13
Table 2

Arginine conc. Coagulating protein conc. Viscosity of

(M) M solution (mPa = s)
0.0 7.5 18.2
0.0 7.9 24.2
0.0 8.8 36.2
0.0 9.7 61.5
0.0 11.1 152.2

0.1 11.1 82.8
0.2 11.1 84.2
0.3 11.1 77.4
0.4 11.1 77.4
0.5 11.1 78.5
Example 1

An example of the application of the tissue adhesive of the
present invention by means of a suitable applicating device will be
described below with reference to the drawing.

Fig. 3 is a plan view of a device suitable for spraying the tissue
adhesive of the present invention. The device for spraying the tissue
adhesive is composed of a syringe (1) containing the fibrinogen solution,
a syringe (2) containing the thrombin solution, a syringe-holding means
(3) for fixing each syringe at its barrel (5 or 6) part, an integrally

operating means (4) placed at the end of a plunger (7 or 8) of each
syringe for operating the plunger (7 or 8), integrally, and a spray head
- 1 1 -


CA 02220927 1997-11-13
(9) at the syringe ends.

As shown in Fig. 3, the cross section of the syringe (1) is larger
than that of the syringe (2). In an embodiment shown in Fig. 3, the
cross section ratio is 5:1 and, therefore, the volume ratio is also 5:1.

The effective stroke, i.e. the distances from the end faces at the exits
(17 or 18) to the inserted pistons (15 or 16) of the two syringes (1 and
2) are equal.

A sterile gas is introduced into a spray head (9) through a
sterilegas-feeding passage (13), and jetted through a sterile gas-jet
opening (14). At the same time, an integrally operating means (4) for

the syringe (1) containing the fibrinogen solution and the syringe (2)
containing the thrombin solution is pressed to extrude both solutions, in
a volume ratio which varies depending on the cross sections of the
Gvri ncrPC in tha form n-F u j' ~h,-.,,,,-.i, the ~i
1 ~--- i -my.ivu.yia a..tic passages in-tlle-spray-1 read (9)

and tubes (11 and 12). The adhesive is thus sprayed.

The syringes (1 and 2) are usually made from glass or a
transparent synthetic resin such as a polypropylene or a polycarbonate.
The syringes (1 and 2) are each composed of a barrel (5 or 6) having a
narrowed part to be connected with the spray head (9) and a smoothly
slidable plunger (7 or 8) inserted into the barrel (5 or 6).

The sterile gas passed through an air filter is fed into the spray
head (9) through the sterile gas-feeding passage (13), and then jetted
through the sterile gas-jet opening (14). In the spray head (9), the
tubes (11 and 12) for feeding the fibrinogen solution and thrombin

solution are arranged from syringe-connecting ports (10) toward the
sterile gas-jet opening(14). Although the materials for the spray head
- 1 2 -


CA 02220927 1997-11-13

(9) are not particularly limited, they are usually soft resins such as
vinyl chloride resin, polyethylene, polyesters and polypropylene, and
metals having a high processability. The tubes (11 and 12) are made of
Teflon, vinyl chloride resin, a metal or the like.

The syringe-holding means (3) is to fix the syringes (1) and (2),
integrally. The shapes of the syringe-holding means (3) can be, various,
and the shape shown in Fig. 3 is one of them. In one face of the
syringe-holding means (3), two grooves having shapes corresponding to the
shapes of the outer walls of the barrels (5 and 6) are formed in parallel.

The depth of the grooves is larger than the radius of the cross section
of the barrel (5 or 6). Therefore, the inlet of the groove is narrow so
that when the barrel (5 or 6) is fixed into the groove, the barrel (5 or
6) will be kept by the grooved wall.

The integrally operating means (4) fixes the pressing parts of the
two plungers (7 and 8) so as to integrally move these plungers (7 and 8)
in the barrels (5 and 6). The shapes of the integrally operating means
(4) can be various, and the shape shown in Fig. 3 is one of them. Two
grooves parallel to each other and keeping plates vertical to the grooves
are integrally molded for fixing the pressing parts of the plungers (7

and 8). The shape of the grooves is almost similar to that of the
grooves of the syringe-holding means (3) so that each pressing part is
fixed in the groove and thereby kept therein. A gap is provided between
the groove and the keeping plate, which varies depending on the pressing
part of the plunger (7 or 8). The syringe-holding means (3) and the

integrally operating means (4) are usually made from a synthetic resin
which is preferably polyethylene, polypropylene, acrylonitrile/
- 1 3 -


CA 02220927 1997-11-13
butadiene/styrene copolymer or a polycarbonate.

The spray coating adhesive for tissue of the present invention is
practically used as follows: The syringe (1) filled with the fibrinogen
solution and the syringe (2) filled with the thrombin solution are fixed

in the syringe-holding means (3). The volume ratio of the fibrinogen
solution to the thrombin solution in the syringes (1 and 2) varies
depending on the cross section of each syringe. A pair of the syringes
(1 and 2) are mounted in the spray head (9). The pressure of the sterile
gas to be jetted is controlled, and the gas is then jetted. Then, the

integrally operating means (4) is slowly pressed with the thumb to
simultaneously apply the fibrinogen solution and the thrombin solution in
a mist form, by means of the sterile gas.

Industrial Utilization:

The tissue adhesive of the present invention is useful for the
adhesion or closing of living tissue of a human being or an animal, when
a strong adhesion and closing effect are demanded in, for example, the
treatment of great vessels and also the treatment of air leak in the
lungs.

25
- 1 4 -

Representative Drawing

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Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date 2008-04-22
(86) PCT Filing Date 1997-03-14
(87) PCT Publication Date 1997-09-18
(85) National Entry 1997-11-13
Examination Requested 2002-03-08
(45) Issued 2008-04-22
Deemed Expired 2013-03-14

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Registration of a document - section 124 $100.00 1997-11-13
Application Fee $300.00 1997-11-13
Maintenance Fee - Application - New Act 2 1999-03-15 $100.00 1999-03-10
Maintenance Fee - Application - New Act 3 2000-03-14 $100.00 2000-02-08
Maintenance Fee - Application - New Act 4 2001-03-14 $100.00 2001-02-02
Maintenance Fee - Application - New Act 5 2002-03-14 $150.00 2002-02-04
Request for Examination $400.00 2002-03-08
Maintenance Fee - Application - New Act 6 2003-03-14 $150.00 2003-01-21
Maintenance Fee - Application - New Act 7 2004-03-15 $200.00 2004-01-21
Maintenance Fee - Application - New Act 8 2005-03-14 $200.00 2005-01-28
Maintenance Fee - Application - New Act 9 2006-03-14 $200.00 2006-02-03
Maintenance Fee - Application - New Act 10 2007-03-14 $250.00 2007-01-17
Maintenance Fee - Application - New Act 11 2008-03-14 $250.00 2008-01-18
Final Fee $300.00 2008-01-25
Maintenance Fee - Patent - New Act 12 2009-03-16 $250.00 2009-01-23
Maintenance Fee - Patent - New Act 13 2010-03-15 $250.00 2010-01-27
Maintenance Fee - Patent - New Act 14 2011-03-14 $250.00 2011-01-20
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
JURIDICAL FOUNDATION THE CHEMO-SERO-THERAPEUTIC RESEARCH INSTITUTE
Past Owners on Record
FUKUNAGA, NOBUTO
KAETSU, HIROSHI
SAKAMOTO, TAKAHIRO
SHINYA, NORIKO
UCHIDA, TAKANORI
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Cover Page 2008-03-27 1 34
Cover Page 1998-02-23 1 36
Abstract 1997-11-13 1 15
Description 1997-11-13 14 499
Claims 1997-11-13 1 30
Drawings 1997-11-13 3 49
Abstract 2006-02-21 1 15
Description 2006-02-21 16 559
Claims 2006-02-21 3 95
Description 2007-03-29 16 555
Claims 2007-03-29 3 85
Assignment 1997-11-13 4 182
PCT 1997-11-13 6 252
Prosecution-Amendment 2002-03-08 1 37
Prosecution-Amendment 2006-09-29 3 128
Prosecution-Amendment 2005-08-18 3 112
Prosecution-Amendment 2006-02-21 14 546
Prosecution-Amendment 2007-03-29 10 390
Correspondence 2008-01-25 2 52
Prosecution-Amendment 2008-01-25 2 52